Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases

Immunity. 2015 Jun 16;42(6):1185-96. doi: 10.1016/j.immuni.2015.04.021.

Abstract

The autoimmune regulator (AIRE) gene is crucial for establishing central immunological tolerance and preventing autoimmunity. Mutations in AIRE cause a rare autosomal-recessive disease, autoimmune polyendocrine syndrome type 1 (APS-1), distinguished by multi-organ autoimmunity. We have identified multiple cases and families with mono-allelic mutations in the first plant homeodomain (PHD1) zinc finger of AIRE that followed dominant inheritance, typically characterized by later onset, milder phenotypes, and reduced penetrance compared to classical APS-1. These missense PHD1 mutations suppressed gene expression driven by wild-type AIRE in a dominant-negative manner, unlike CARD or truncated AIRE mutants that lacked such dominant capacity. Exome array analysis revealed that the PHD1 dominant mutants were found with relatively high frequency (>0.0008) in mixed populations. Our results provide insight into the molecular action of AIRE and demonstrate that disease-causing mutations in the AIRE locus are more common than previously appreciated and cause more variable autoimmune phenotypes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Autoimmunity / genetics
  • Child
  • Child, Preschool
  • DNA Mutational Analysis / methods*
  • Female
  • Gene Frequency
  • Genes, Dominant / genetics*
  • Humans
  • Male
  • Microsatellite Repeats / genetics
  • Molecular Sequence Data
  • Mutation / genetics*
  • Norway
  • Organ Specificity / genetics
  • Pedigree
  • Penetrance
  • Phenotype
  • Polyendocrinopathies, Autoimmune / genetics*
  • Russia
  • Transcription Factors / genetics*
  • Young Adult

Substances

  • APECED protein
  • Transcription Factors

Supplementary concepts

  • Autoimmune polyendocrinopathy syndrome, type 1